The goal of radiation therapy is to maximize tumor control while minimizing complications. This axes of this graph represent Dose on the X-axis and tumor control or complications to normal tissues on the Y-axis. With respect to tumor control, as dose increases, the chance of tumor control increases. Likewise as dose increases, so does the probability of complication (represented by the red curve). Both these curves are sigmoidal in shape. Initially with low doses, there is little cell kill, and hence little tumor control. At a certain dose, the probability of cell kill increases dramatically, and hence high tumor control. However, beyond a certain dose, the curve again flattens so that increases in dose (while still toxic to tumor), does not increase the probability of further cell killing beyond what a lower dose can achieve. The risk of complication follows this same paradigm. Low dose has little chance of causing complication. However, at certain doses, the complication rate climbs sharply. These curves tend to be parallel, and the goal of radiation oncology is to maximize the potential for tumor killing (or tumor control) while minimizing the potential for normal tissue complications. The white vertical dashed line represents this compromise in therapeutic efficacy to achieve maximal tumor control with minimal normal tissue complication.
Ceramide is the central regulator of apoptosis both in the vascular endothelial cells as well tumor cells. Pharmacologic therapy can be targeted to increase the levels of ceramide in the cells in order to increase radiosensitivity (such as VEGF inhibitors).
Emphasize that RPA Class I and II have the same KPS
Neurologic impairment is very common in brain metastasis patients at presentation, before any sort of treatment is initiated. The bars represent seven neurocognitive tests. The first two, PEG-D and PDG-ND stand for pegboard dominant hand and pegboard non-dominant hand. In this test a patient is given a pegboard with different shapes of pins to insert. The test is timed to see how many pins they can put in. At diagnosis, almost 2/3 of patients are impaired in motor function. The next two bars are recall and delayed memory tests; almost 60% of patients are impaired in these memory tests. The last bar is also a memory test, but for recognition. The bar after delayed memory is a test of executive function that looks at trail-making. Patients are given a sheet of paper with random letters and numbers and are asked to connect the letters to the numbers in terms of their order in the alphabet (e.g., connect 1A, B2, C3, etc.). This is called “executive function” as several abilities are required, including reading, fine motor control, and thought processing. COWA stands for controlled oral word association, which tests verbal fluency. For example, a patient will be given the letter “c” and asked to name words that start with that letter. Or they might be given 20 words and be asked to repeat them. The take-home message is that all of these tests show that many patients have neurologic impairment at the time of diagnosis.
Retrospective review of more 500 patients from 10 institutions comparing patients who received whole brain radiation therapy with those who didn’t. Patients were classified into three groups, RTOG/RPA class 1, 2 or 3. In each class there are three bars. The first bar represents patients undergoing radiosurgery only. This is the median survival. The second bar represents patients who received both radiosurgery and whole brain radiotherapy. There is effectively no difference in the combination. The third bar represents patients who received whole brain radiotherapy, only. Both the radiosurgery bars are better than the whole brain radiation bar, alone. The conclusion from this study was that delayed whole brain radiotherapy did not worsen overall survival.
including asymptomatic cases discovered And one autopsy study looking at combined spinal and intracranial meningiomas found that 2.3% of individuals harboured undiagnosed asymptomatic meningiomas (1000X more common than clinically detected) Brain MRI in Vienna in 532 asymptomatic subjects >75 y.o found incidental meningiomas in 1 out of 35 women
02 suh srs hyderabad 2013 (cancer ci 2013) john h. suh
Overview of Stereotactic Radiosurgery for Brain Tumors John H. Suh, M.D. Professor and Chairman, Dept. of Radiation Oncology Associate Director of the Gamma Knife Center Rose Ella Burkhardt Brain Tumor and Neuro-oncology Center Taussig Cancer Institute
Conflict of interest• Abbott Oncology Consultant• Varian Travel funds
Outline• Review the history of stereotactic radiosurgery (SRS)• Discuss the role of SRS for brain metastases• Review the results of SRS for benign brain tumors
Therapeutic Index 100Tumor control (%) Control 50 Complications 0 Dose (Gy)
Radiobiology of Radiosurgery Balagamwala E, Chao S, Suh J. Tech Ca Res Treat 2012
Linac Radiosurgery at CCF -- 1989- 1997• Adapt linear accelerator• Base plate and floor stand• Shotgun collimator• Rotate gantry and table position to deliver 5 non- coplanar arcs• First program in Ohio Presentation Title l l 9
Computerized plan for linac-based radiosurgery Presentation Title l l 10
Epidemiology of Brain Metastases Primary Tumor Relative Prevalence of Brain Metastases* Colon: 5% Annual U.S. incidence: > 170K Ratio Mets/Primary: 10:1 Melanoma: 9% All Cancer Patients: 15 - 30% Autopsy incidence: 10 - 30% Unknown primary: 11% Mean age: 60 years Median survival: 4-6 months Other known primary: 13% Breast: 15% Lung: 48%*Incidence increasing with better systemic Rx and improved survival Wen PY, et al. In: DeVita VT Jr, et al (eds). Cancer: Principles & Practice of Oncology. 2001:2656-2670.
Factors Used to Assess Therapy • Number of metastases • Size of lesion(s) • Location • Neurological deficits • Age / KPS • Primary tumor / stage • Extracranial disease • Patient’s input
Brain Metastases: Recursive Partitioning Analysis Class I Class II Class III KPS ≥70 KPS ≥70 KPS <70 KPS ≥ 70 Primary: Primary: Controlled Uncontrolled and / or Age: <65 Age: ≥65 and / or Extracranial Extracranial metastases: No metastases: Yes MST 7.1 m MST 4.2 m MST 2.3 m 20% 65% 15% Gaspar L, et al., Int J Radiat Oncol Biol Phys. 1997;37:745-51
Graded Prognostic Assessment (GPA) for brain metastases Evaluated 1960 patients from five randomized RTOG studies Develop a less subjective, more quantitative, easier to use Score Median survival (months) 0 0.5 1.0 3.5-4 11.0Age >60 50-59 <50 3 6.9KPS <70 70-80 90-100 1.5-2.5 3.8Number of CNS >3 2-3 1 0-1 2.6metastasesExtracranial Present - Nonemetastases Sperduto P et al Int J Radiat Oncol Biol Phys 70:510, 2008
WBRT-Alternative Fractionation Regimens Lack of Progress Randomization MST Study N (Total Dose/# Fractions) (months)Harwood et al. (’77) 101 30/10 vs. 10/1 4.0-4.3Kurtz et al. (’81) 255 30/10 vs. 50/20 3.9-4.2Borgelt et al. (’81) 138 10/1 vs. 30/10 vs. 4.2-4.8 40/20Borgelt et al. (’81) 64 12/2 vs. 20/5 2.8-3.0Chatani et al. (’85) 70 30/10 vs. 50/20 3.0-4.0Haie-Meder et al. 216 18/3 vs. 36/6 vs. 43/13 4.2-5.3(’93)Priestman et al. (’96) 30/10 vs. 12/2 2.5-2.8Murray et al. (’97) 445 54.4/34 vs. 30/10 4.5
Side Effects of WBRT• Alopecia• Fatigue• Skin erythema• Headache• Otitis media• Somnolence syndrome• Memory loss• Radiation necrosis• Leukoencephalopathy
Patients Impaired at Presentation 70 Motor Function Memory N=401 60 Impairment = Z ≥ 1.5 Executive 50 FunctionPercentage 40 Fluency 30 Memory 20 10 0 Trail B Recog Delay Recall Peg D Peg ND COWA Peg D Peg ND Recall Delay Trail B COWA Recog Brain met patients have high rates of baseline deficits Meyers CA, et al. J Clin Oncol. 2004;22:157-165.
Favorable Characteristics of Brain Metastases for SRS • Radiographically distinct on MRI/CT • Pseudospherical shape • Displaces normal brain tissue • Minimal invasion of normal brain • Size at presentation ≤3 cm
Radiosurgery without WBRT 18 16.3 16.2 RS 16 RS/WBRT 14 RTOG 12 Months 10 8.6 7.9 8 7.1 5.5 6 5.1 4.2 4 2.3 2 0 Class I Class II Class III 272 pts RS only upfront 388 RS + WBRT (non-randomized) (10-institution retrospective study) Delayed WBRT does not worsen survivalneed, PK, Suh JH, et al. Int. J Radiat Oncol Biol Phys. 53:519-526, 2002.
RTOG 95-08 RS Number of A Arm 1: Whole brain RT to 37.5 Gy/15 fractions/2.5 GyT Metastases N once daily, 5 days/ 1. SingleR 2. 2-3 D week followed by radiosurgery to all (1-3)A O metastasesT Extent of M Extracranial diseaseI 1. None I Arm 2: Whole brain RT to 37.5F 2. Present Z Gy/15 fractions/2.5 GyY once daily, 5 days/ E week
KAPLAN-MEIER SURVIVAL RTOG 9508 Survival Single Brain Metastasis 100 — RT + SRS MST = 6.5 mo Percentage alive 80 --- RT Alone MST = 4.9 mo 60 p = 0.047 40 20 0 0 6 12 18 24 Months Andrews DW et al. Lancet 363:1665-1672, 2004
Phase III randomized trial of SRS +/-WBRT No prior surgery, SRS, or WBRT No leukemias, lymphomas, germ-cell tumors, SCLC, leptomeningeal diseaseRPA class I /IIpatients with R R SRS (15, 18 or 24 Gy) 1-3 lesions A A from known primary N N D SRS + WBRT (30 Gy/12 fx) 58 pts D Stratification by – RPA class (I or II) – number of lesions (1 or 2 vs 3) – “radioresistant” histologies (melanoma or RCC vs other) ? Baseline neurocognitive function and medications (opioids, sedatives) Primary endpoint: neurocognitive function – Defined as a decrease in HVLT-R total recall at 4 months by more than 5 points – Trial was closed early by data monitoring committee Chang EL et al. Lancet Oncol 2009:10:1037-1044
Neurocognitive decline“A mean posterior probability of [neurocognitive] decline of 52% for the SRS plusWBRT group and 24% for the SRS only group.” (96% confidence) Chang EL et al. Lancet Oncol 2009:10:1037-1044
Phase III randomized trial of surgery or SRS +/-WBRT EORTC 22592-26001 RPA class I /II patients Rwith 1-3 brain R Observation Surgery A with stable Asystemic dz or SRS N N WBRT 30 Gy/10 fxasymptomatic 359 pts D D primary WHO PS 0-2 Primary endpoint: deterioration to WHO PS > 2 Eligibility: single < 3.5 cm; 2-3 lesions < 2.5 cm PTV = 1-2 mm margin Dose 25 Gy to center with minimum dose of 20 Gy. Kocher M et al. J Clin Oncol 29:134-141, 2010
Phase III randomized trial of surgery or SRS +/-WBRT EORTC 22592-26001 Observation WBRT p value Median time WHO PS > 2 10 m 9.5 m 0.71 Median overall survival 10.9 m 10.7 m 0.89 2-year relapse at initial site Surgery 59% 27% 0.001 SRS 31% 19% 0.04 2-year relapse at new sites Surgery 42% 23% 0.008 SRS 48% 33% 0.023 Kocher M et al. J Clin Oncol 29:134-141, 2010
NCCTG N0574(Intergroup) PE, <2.0 cm 24 Gy Patients with R QOL, 2 - 2.9 cm 20 Gy F & histologically A Related O confirmed Arm 1: N A L extra-cerebral S RS* primary tumor D S Land 1 to 3 brain O E O S metastases M S Arm 2: W detected by I M RS* + WBRT MRI Z E (30 Gy/12 fx) U N E T <2.0 cm 22 Gy P S 2 - 2.9 cm 18 Gy 152 pts
SRS of the Post-Operative Cavity• 72 patients treated at Stanford from 1998-2006• PTV = GTV in 76%• 1y LC: 79% GTR vs. STR .52 Histology .49 Number of Fractions .92 Dose .92 BED .92 Conformity Index .04 Volume .29 Based on result, using 2 mm margin on GTV Soltys S et al. Int J Radiat Oncol Biol Phys 70, 2008
N107C SRS vs. WBRT Resected Brain Mets Determine if neurocog progression less at 6 months with SRS Age <60 vs. >60 S # Brain Mets R T 1 vs. 2-4 A SRS Surgical Bed + SRS toResected R N unresected brain metastases Extracranial Dz D Brain A Met T O Histology I Lung vs. M WBRT* + SRS to unresected+ F Radioresistant I SRS to unresected Y vs. Others Z metastases E Surgical Cavity <3 vs. > 3 cm *37.5 Gy/15 fx 192 patients
Results with SRS for multiple brain metastases Suh JH, et al. J Stereo Radiosurg SBRT 1:31-40, 2011
Challenge of radiation necrosis after SRSDiagnosis and Treatment
Introduction: Meningiomas• Most common primary intracranial neoplasm• ~30% of all intracranial neoplasms• Estimated prevalence is 97.5 per 100,000• Most are identified on imaging alone• F:M – 2:1 supratentorial Klaus et al. Neurosurg 57:1088, 2005 Central Brain Tumor Registry 2007
Meningioma EPIDEMIOLOGY Most Common Brain and CNS Tumors by Age CBTRUS Statistical Report: NPCR and SEER Data 2004-2006 Age (yrs) Most Common Histology 2nd Most Common Histology 0-4 Embryonal / Medulloblastoma Pilocytic Astrocytoma 5-9 Pilocytic Astrocytoma Malignant Glioma , NOS 10-14 Pilocytic Astrocytoma Neuronal / Glial 15-19 Pituitary Pilocytic Astrocytoma 20-34 Pituitary Meningioma 35-44 Meningioma Pituitary 45-54 Meningioma Glioblastoma 55-64 Meningioma Glioblastoma 65-74 Meningioma Glioblastoma 75-84 Meningioma Glioblastoma 85+ Meningioma Neoplasm, unspecifiedCBTRUS Statistical report: primary brain and central nervous system tumors diagnosed in the United States 2004-2006. http://www.cbtrus.org/2010-NPCR-SEER/CBTRUS-WEBREPORT-Final-3-2-10.pdf. February 2010 Courtesy of L. Rogers
Meningioma Likelihood of total excision Historical MGH experienceTumor Location n % Total Excision 96 %Convexity 47Orbit 5 80 %Spine 18 78 %Olfactory Groove 22 77 %Parasagittal Area/Falx 38 76 %Parasellar Region 28 57 %Posterior Fossa 31 32 %Sphenoid Ridge 36 28 % TOTAL: 225 64% Mirimanoff et al, J Neurosurg 62: 18 – 24, 1985
Meningioma Recurrence-Free Survival by Grade (643 pts) 100 5-yr RFS 90 88% Benign, n=464 (72.1%) 80 70 59%Percent 60 50 Atypical, n=156 (24.3%) * 40 28% 30 Anaplastic, n=23 (3.6%) 20 p < 0.001 10 0 0 1 2 3 4 5 6 7 8 9 10 Years Arie Perry et al, Am J Surg Pathol 21:1455-1465, 1997 & Cancer 85:2046-2056, 1999
RTOG - 0539 Schema Phase II Study of IMRT for Intermediate and High Risk Meningiomas, and Observation for Low Risk Meningiomas Group 1 (Low Risk): New Grade 1, GTR or STR Group 2 (Interm Risk): Recurrent Grade 1, GTR or STR New Grade 2, GTR Group 3 (High Risk): Any Grade 3 Recurrent Grade 2 New Grade 2, STRPrimary endpoint: 3 yr PFS Group 1 Observation Group 2 Strata 3D-CRT/IMRT 54 Gy / 30 fxs Group 3 IMRT 60 Gy / 30 fxs
Current EORTC 22042-26042 TrialAdjuvant postoperative high-dose radiotherapy foratypical and malignant meningioma: a Phase II and observation study
University of Pittsburgh: long term results• Updated their 18-year experience in a cohort of 972 patients with 1045 intracranial meningiomas• 70% women• 645 patients had middle and posterior fossa tumors• Median dose 14 Gy Kondziolka D, et al. Neurosurg 62(1):53-8, 2008
University of Pittsburgh: long term results• Among 75 patients with a minimum follow-up of 10 years, the local control rates for grade 1 meningiomas or lesions without histology were 91% and 95%, respectively.• Local control for WHO II and III were 50% and 17%, respectively.• Symptomatic peritumoral edema was 4 months at mean of 8 months. Kondziolka D, et al. Neurosurg 62(1):53-8, 2008
Treatment options for Pituitary Tumors• Observation• Microsurgery• Medical• Radiosurgery• Radiation therapy• Multimodality approachDepends on symptoms, tumor sizeat presentation, involvement ofadjacent structures, and vicinity tooptic apparatus
Indications for radiation therapy and radiosurgery • Primary therapy • Adjunctive therapy • Salvage therapy
Pituitary adenoma 20 Gy (13 shots- 16, 8 mm with Blocking)Optic chiasm dose 7.9 Gy
Epidemiology of Vestibular Schwannomas• 2000-3000 new cases of VS diagnosed per year in the U.S., an incidence of 1/100,000 per year• 8-10% of all primary intracranial tumors• 80-90% of all cerebellopontine angle tumors• Commonly present between 30-50 year of age• Can be associated with NF-2• Incidence of occult VS in human temporal bones: 0.57-0.87%
SRS vs FSR: Jefferson Results •Retrospective study of 125 patients with AN •69 treated with SRS (12 Gy to the 50% IDL) •56 treated with FSR (50 Gy/25 fx) Tumor Preserv Preserv Preserv Tumor Control Control Trigem Facial Hearing NF2SRS 98% 95% 98% 33% 80%FSR 97% 93% 98% 81% 67%P value 0.6777 0.5893 0.8202 0.0228 0.6615 Dosing recommendation: 46.8 Gy/26 fx Andrews D, et al., Int J Radiat Oncol Biol Phys 2001; 50:1265-1278
SRS vs FSR from Netherlands•All treatments were linac-based from 1992 to 1999•129 patients prospectively randomized to SRS vs. FSR –Dentate: FSR (20 Gy/5 fx and 25 Gy/5 fx) –Edentate: SRS (10 Gy and 12.5 Gy)•Mean Tumor Diameter (FSR: 2.5 cm vs. SRS: 2.6 cm) Local Control Preserved Preserved VII Preserved Vth Hearing Function FunctionFSR 94% 61% 97% 98%SRS 100% 75% 93% 92% Meijer et al. Neurosurg 2003; 56(5): 1390-1396
SRS versus FSRT for vestibular schwannomas 200 patients treated at Heidelberg and DFKZ Hearing preserv SRS <13 Gy and FSRT 57.6 Gy/32 fx <13 Gy FSRT SRS >13 Gy Combs S, et al. Int J Radiat Oncol Biol Phys 76:193-200, 2010
Conclusions• Stereotactic radiosurgery (SRS) is a safe and effective treatment option for a variety of brain tumors.• The use of SRS for brain metastases is increasing.• SRS is an effective treatment option for patients with brain metastases.• SRS is an effective and safe treatment option for patients with benign brain tumors
Title of Presentation Arial Regular 22ptSingle line spacingUp to 3 lines longDate 20ptsAuthor Name 20ptsAuthor Title 20pts